17 β-carboxanilides of 4-aza-5α-androstan-3-ones as 5α-reductase inhibitors

ABSTRACT

Described are new 17β-carboxanilides of 4-aza-5α-androstan-3-ones and related compounds of structural formula I: ##STR1## and the use of such compounds as 5α-reductase inhibitors for treatment of benign prostatic hyperplasia acne, seborrhea, female hirsutism, prostatitis, and prostatic carcinoma and other hyperandrogenetic related disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is national phase application under 35 U.S.C §371 ofPCT application Ser. No. PCT/US93/09585, filed Oct. 6, 1993, publishedas WO94/07861 Apr. 14, 1994, which, in turn is a continuation in part ofapplication Ser. No. 07/957,231 filed Oct. 6, 1992, now abandoned.

BACKGROUND OF THE INVENTION

The present invention is directed to new 17β-carboxanilides of4-aza-5α-androstan-3-ones and related compounds and the use of suchcompounds as 5α-reductase inhibitors.

DESCRIPTION OF THE PRIOR ART

The art reveals that certain undesirable physiological manifestations,such as acne vulgaris, seborrhea, female hirsutism, male patternbaldness and benign prostatic hyperplasia, are the result ofhyperandrogenetic stimulation caused by an excessive accumulation oftestosterone or similar androgenic hormones in the metabolic system.Early attempts to provide a chemotherapeutic agent to counter theundesirable results of hyperandrogenicity resulted in the discovery ofseveral steroidal antiandrogens having undesirable hormonal activitiesof their own. The estrogens, for example, not only counteract theeffect, of the androgens but have a feminizing effect as well.Non-steroidal antiandrogens have also been developed, for example,4'-nitro-3-trifluoromethyl-isobutyranilide. See Neri, et at., Endo.,Vol. 91, No. 2 (1972). However, these products, though devoid ofhormonal effects, compete with all natural androgens for receptor sites,and hence have a tendency to feminize a male host or the male fetus of afemale host and/or initiate feed-back effects which would causehyperstimulation of the testes.

It is now known in the art that the principal mediator of androgenicactivity in some target organs, e.g. the prostate, is5α-dihydrotestosterone, and that it is formed locally in the targetorgan by the action of testosterone-5α-reductase. It is also known thatinhibitors of testosterone-5α-reductase will serve to prevent or lessensymptoms of hyperandrogenetic stimulation.

For example, a number of 4-aza steroid compounds are known which are5α-reductase inhibitors. See the following Merck & Co., Inc. patents,U.S. Pat. Nos. 4,377,584, 4,220,775, 4,859,681, 4,760,071 and thearticles J. Med. Chem. 27, p. 1690-1701 (1984) and J. Med. Chem. 29,2998-2315 (1986) of Rasmusson, et al., and U.S. Pat. No. 4,845,104 toCarlin, et al., and U.S. Pat. No. 4,732,897 to Cainelli, et at., and EPPublication No. 0 484 094 to Sankyo, which describe4-aza-17β-substituted-5 α-androstan-3-ones said to be useful in thetreatment of DHT-related hyperandrogenic conditions.

However, none of the above references specifically describe thecompounds of the instant invention, which are selective and potentinhibitors of 5α-reductase in humans, as well as animals, i.e. dogs,which are exceptionally active.

SUMMARY OF THE INVENTION

The present invention discloses novel anilide derivatives of17β-carboxy-4-aza-5α-androstan-3-ones which are useful for inhibitingthe 5α-reductase enzyme in prostatic tissue and isozymes thereof. Theyare also particularly effective in selectively inhibiting mammalian5α-reductase for the treatment of benign prostatic hyperplasia in humansand dogs, acne, female hirsutism, androgenic alopecia, i.e., malepattern baldness and treatment of prostatic carcinoma.

In accordance with the present invention there is provided novelanilides of 17β-carboxy-4-aza-5α-androstan-3-one and related compoundsof the formula: ##STR2## wherein:

R is H, CH₃, or C₂ H₅ ;

R₁ is H, C₁ -C₁₀ alkyl, or phenyl; and

X, Y and Z independently represent --H; --OH; --NH₂ ; SH; --SC₁ -C₄alkyl;

--CO₂ H; --CN; --C₂ -C₁₀ acyl; --C₇ -C₁₅ aroyl; straight or branchedchain alkyl having 3, 4, 5, 6, 7, or 8 carbon atoms; --C₃ -C₈cycloalkyl; -C₆ -C₁₄ aryl; heteroaryl; heteroaroyl; --C₇ -C₁₀ aralkyl;--CONR² R³ where R² and R³ independently are H, C₁₋₈ alkyl, C₃₋₈cycloalkyl, C₆ -C₁₄ aryl, or R² and R³ together with the nitrogen towhich they are attached form a 5-7 membered saturated heterocyclic ringcontaining 1-2 nitrogen atoms, and 0-1 oxygen atoms;

--NHCOR² ;

--OCOR² ;

--NR² (CO)R³ ;

--NR² (CO)NHR³ ;

--NHSO₂ R² ;

--OR² ;

--NR² R³ ;

--CO₂ R² ;

provided that X, Y, and Z cannot simultaneously be --H when R¹ is --H orC₁ -C₁₀ alkyl, and provided further that X, Y, and Z cannotsimultaneously be --H when R¹ is phenyl and R⁴ is --H or methyl; and

wherein the aryl, aroyl, heteroaryl, and heteroaroyl substituents can beunsubstituted or substituted by 1-3 substituents as defined above for X,Y and Z;

R⁴ can be:

1) oxo;

2) alpha-hydrogen and beta-hydrogen or a beta-substituent selected from:C₁ -C₄ alkyl; C₂ -C₄ alkenyl; --CH₂ COOH; hydroxy; carboxy; --COOC₁ -C₄alkyl esters; --OCONR⁵ R⁶, wherein R⁵ and R⁶ are independently H, C₁ -C₄alkyl, phenyl, benzyl, or R₅ and R₆ together with the nitrogen to whichthey are attached can form a 5-6 membered saturated heterocyclic ring,optionally containing one other heteroatom; --OC₁ -C₄ alkyl; --OC₃ -C₆cycloalkyl; --OCOCH₃ ; halo; hydroxy C₁ -C₂ alkyl; halo C₁ -C₂ alkyl;trifluoromethyl; and C₃ -C₆ cycloalkyl;

3) =CH--R' where R' is H, or C₁ -C₄ alkyl;

4) spiro: ##STR3## where R' is H, or C₁ -C₄ alkyl; and wherein thedashed line can represent a double bond when present; andpharmaceutically acceptable salts and esters thereof.

Also disclosed are processes for their preparation, pharmaceuticalformulations comprising the novel compounds as active ingredients andmethods of inhibiting 5α-reductase in diseases which occur underhyperandrogenetic conditions, e.g., benign prostatic hyperplasia.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The structure I above encompasses all the 5α-reductase inhibitorcompounds of this invention.

The dashed line can independently be a double bond and, when present,the compound is a delta-1-ene.

The aryl ring of the anilide can be unsubstituted or substituted withone or more of the following substituents indicated by X, Y and Z,providing the substitution leads to a chemically stable, butbiologically active 5α-reductase inhibitor.

By the term "C₁ -C₄ alkyl" is meant linear or branched alkyl; e.g.methyl, ethyl, isopropyl, propyl, n-butyl, isobutyl, sec-butyl and thelike.

By the term "hydroxy C₁ -C₂ alkyl" is meant monohydroxy C₁ -C₂ alkylincluding: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and the like.

By the term "halo C₁ -C₂ alkyl" is meant mono halogenated C₁ -C₂ alkylincluding: fluoromethyl, chloromethyl, 1-fluoroethyl, 2-fluoroethyl,1-chloroethyl, 2-chloroethyl, and the like.

By the term "OC₁ -C₄ alkyl" as used herein is meant to include methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy,and the like.

By the term "OC₃ -C₆ cycloalkyl" as used herein is meant to include:cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

C₂ -C₄ alkenyl includes ethenyl, allyl, 1- and 2-butenyl and the like.

C₃ -C₆ cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like.

"Halo" includes fluoro, chloro, bromo and preferred is fluoro, chloro.

R₅ and R₆ can also be connected to form a 5-6 membered heterocyclicradical, being fully saturated, containing 1-2 nitrogen atoms and 0-1oxygen atoms, e.g., piperidino, pyrrolidino, morpholino, and the like.

The phenyl and benzyl groups in R₅ and R⁶ can be unsubstituted orsubstituted with one or more of the following substituents providing thesubstitution leads to a chemically stable, but biologically active5-alpha reductase inhibitor:

The ring substituents include:

C₁ -C₄ straight or branched alkyl;

C₁ -C₅ alkoxy; and

halo; all as defined above.

Representative examples of R⁴ are where the α-substituent (dashed lines)is hydrogen and the beta substituent (wedge) is e.g. methyl, ethyl,propyl, allyl, carboxymethyl, hydroxy, methoxy, ethoxy, cyclopropyloxy,cyclopentyloxy, acetoxy, fluoro, chloro, bromo, trifluoromethyl,trichloromethyl, fluoromethyl, chloromethyl, carboxy,N,N-dimethylcarbamate, hydroxymethyl, methoxymethyl, and the like.

Representative examples where R⁴ is an alkenyl substituent, =CH--R',includes, e.g. =CH₂, =CH--CH₃, =CH--CH₂ CH₃, and the like.

Representative examples where R⁴ is the spiro substituent: ##STR4##stereoisomers thereof and the like.

By the term "C₁ -C₁₀ alkyl" is meant linear or branched alkylhydrocarbon; e.g. methyl, ethyl, isopropyl, propyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, n-hexyl, iso-hexyl, n-octyl, iso-octyl,t-octyl, n-decyl, and the like.

By the term "C₁ -C₈ alkyl" is meant a saturated straight or branchedchain hydrocarbon radical containing 1-8 carbons including thosedescribed above.

By the term "C₃ -C₈ cycloalkyl" is meant e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 1-methyl-cyclobutyl, cyclopentyl, cyclohexyl,1-methyl-cyclohexyl, 2-methylcyclohexyl, 2-ethylcyclohexyl, and thelike;

By the term "C₂ -C₁₀ acyl" is meant C₁ -C₉ alkylcarbonyl, includingacetyl, n-propionyl, iso-butyryl, n-decanoyl, and the like.

By the term "C₇ -C₁₅ aroyl" is meant arylcarbonyl, including benzoyl,naphthoyl and anthranoyl.

By the term "C₆ -C₁₄ aryl" is meant a mono or polycyclic carbocyclicaromatic radical, including phenyl, naphthyl, anthranyl, and the like.

By the term "C₇ -C₁₀ aralkyl" is meant a phenyl substituted C₁ -C₃ alkylchain including benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl andthe like.

The anilide phenyl ring substituents in addition to those above include:

"heteroaryl" being a 5-7 membered aromatic ring containing 0-4 nitrogenatoms and 0-1 oxygen or 0-1 sulfur atoms, which can be 1,2-fused with abenzo ring or another heteroaryl ring as defined above; included in thisdefinition are the following:

pyridyl, furyl, pyrryl, thienyl, isothiazolyl, imidazolyl,benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl,purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl, andbenzoxazolyl, and the like, which can be further substituted by 1-3 ofX, Y and Z as defined herein;

"heteroaroyl" including the above described heteroaryl rings attached toa --C(=O)-- group including:

pyridoyl, furoyl, pyrroyl, thienoyl, isothiazoloyl, imidazoloyl,benzimidazoloyl, tetrazoloyl, pyrazinoyl, pyrimidoyl, quinoloyl,isoquinoloyl, benzofuroyl, isobenzofuroyl, benzothienoyl, pyrazoloyl,indoloyl, isoindoloyl, purinoyl, carbazoloyl, isoxazoloyl, thiazoloyl,oxazoloyl, benzthiazoloyl, benzoxazoloyl, and the like, which can befurther substituted by 1-3 of X, Y and Z as defined herein;

--CONR² R³, where R² and R³ independently are H, C₁ -C₈ alkyl, C₃ -C₈cycloalkyl, C₆ -C₁₄ aryl, all as defined above; and together they canform a 5-7 membered saturated heterocyclic ring containing 1-2 nitrogenatoms, and 0-1 oxygen atoms, e.g. piperidino, piperazino, pyrrolidino,morpholino;

--NHCOR², including acetylamino, isobutyrylamino, n-octanoylamino,2-adamantanoylamino, 2-pyridylcarbonyl-amino, pivaloylamino,benzoylamino, and the like;

--OCOR², including acetoxy, propionoyloxy, cyclopropanecarboxy,2-adamantanecarboxy, t-butanecarboxy, 2-pyridocarboxy, and the like;

--NR² (CO)R³, including formylamino, acetylamino, butyrylamino,benzamido, 2-adamantanecarboxamido, benzoylamino, and the like;

--NR² (CO)NHR³, including ureido, N1-benzylureido, N1-ethylureido,N2-methylureido, and the like;

--NHSO₂ R², including phenylsulfonamido, methylsulfonamido,benzylsulfonamido, toluenesulfonamido, trifluoromethanesulfonamido, andthe like;

--OR², including methoxy, ethoxy, phenoxy, cyclopropoxy, t-butoxy, andthe like;

--NR² R³, including methylamino, ethylamino, dimethylamino,diethylamino, diisopropylamino, pyrrolidino, morpholino, and the like;

--CO² R², including methoxycarbonyl, ethoxycarbonyI, t-butoxycarbonyl,benzoxycarbonyl, 2-adamantoxycarbonyl, and the like.

In addition, C₇ -C₁₅ aroyl and C₆ -C₁₄ aryl can be substituted by 1-3 X,Y or Z substituents as defined herein.

Preferably the anilide ring is monosubstituted, with one of theabove-described substituents where at least two of X, Y or Z are H, orwhere the anilide phenyl ring is completely unsubstituted.

Any substitutions which result in the formation of compounds containingquaternary nitrogen atoms are not intended to be within the scope of thepresent invention.

Representative compounds of the present invention include the following:

N-(4-hydroxyphenyl)-3-oxo-4-aza-5α-androst-1-ene-17 β-carboxamide, mp.325° C.(d);

N-(3-hydroxyphenyl)-3-oxo-4-aza-5α-androst-1-ene-17 β-carboxamide, mp.289°-291° C.;

N-(2-hydroxyphenyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, mp.297°-299° C.;

N-phenyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, mp. 293°-295° C.;

N-(4-aminophenyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, mp.277°-279° C.;

N-(3-aminophenyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, mp.227°-228° C.;

N-(2-aminophenyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, mp.274°-276° C.;

N-phenyl-3-oxo-4-methyl-4-aza-5α-androst-1-en-17β-carboxamide,

N-phenyl-3-oxo-4-aza-5α-androstane-17β-carboxamide, mp.285°-287° C.;

N-phenyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide,

N-phenyl-3-oxo-4-methyl-4-aza-5α-androstane-17β-carboxamide, mp.281°-283° C.;

N-phenyl-3-oxo-7β-methyl-4-aza-5α-androstane-17β-carboxamide,

N-phenyl-3-oxo-4,7β-dimethyl-4-aza-5α-androstane-17β-carboxamide,

N-(4-carbomethoxy)phenyl-3-oxo-4-aza-5α-androstane-17β-carboxamide, mp.287°-289° C.;

N-(4-carbomethoxy)phenyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide,mp. 265°-267° C.;

N-(4-carboxyphenyl)-3-oxo-4-aza-5α-androstane-17β-carboxamide, mp.355°-357° C.;

N-(4-carbomethoxy)phenyl-N-methyl-3-oxo-4-methyl-4-aza-5α-androstane-17β-carboxamide,mp. 149°-150° C.;

N-(4-carbomethoxy)phenyl-N-methyl-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,mp. 96°-98°;

N-(2-carbomethoxy)phenyl-3-oxo-4-aza-5α-androstane-17β-carboxamide, mp.128°-129° C.;

N-(2-methoxycarboxy)phenyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide,mp. 115°-116° C.;

N-(4-aminophenyl)-3-oxo-4-aza-5α-androstane-17β-carboxamide, mp. 295°C.;

N-(4-aminophenyl)-3-oxo-4-methyl-4-aza-5α-androstane-17β-carboxamide,mp. 304°-307° C.(d);

N-4-acetamidophenyl-N-acetyl-3-oxo-4-methyl-4-aza-5α-androstane-17.beta.-carboxamide,mp. 335°-336° C.;

N-4-acetamidophenyl-3-oxo-4-methyl-4-aza-5α-androstane-17β-carboxamide,mp. 144°-147° C.;

N-4-acetamidophenyl-3-oxo-4-aza-5α-androstane-17β-carboxamide mp.335°-336° C.;

N-4-pivalamidophenyl-3-oxo-4-methyl-4-aza-5α-androstane-17β-carboxamide,mp. 296°-298° C.;

N-4-isobutyramidophenyl-3-oxo-4-methyl-4-aza-5α-androstane-17β-carboxamide,mp. 260°-261° C.,

and also including the corresponding compounds wherein the 4-hydrogensubstituent is replaced by a methyl or an ethyl radical, and where adelta-one double bond is present.

Also included within the scope of this invention are pharmaceuticallyacceptable salts, i.e. hydrochloride, hydrobromide, acetate, pamoate,and the like, which can be used as the dosage form for modifyingsolubility or hydrolysis characteristics or for use as sustained releaseor prodrug formulations.

Accordingly, the present invention is particularly concerned withproviding a method of treating the hyperandrogenic conditions of acnevulgaris, seborrhea, female hirsutism as well as benign prostatichyperplasia, prostatitis, and prostatic carcinoma by oral or parenteraladministration of the novel compounds of the present invention.

The present invention is thus also concerned with providing suitabletopical, oral and parenteral pharmaceutical formulations for use in thenovel methods of treatment of the present invention.

The compositions containing the compounds of the present invention asthe active ingredient for use in the treatment of benign prostatichypertrophy can be administered in a wide variety of therapeutic dosageforms in conventional vehicles for systemic administration, as, forexample, by oral administration in the form of tablets, capsules,solutions, or suspensions, or by intravenous or intramuscular injectionor by subdermal implantation, i.e., in the male dog. The dosage of theproducts for an adult human/per day or for a male dog can be varied overa wide range varying from 0.5 to 1,000 mg. The compositions arepreferably provided in the form of scored tablets containing 0.5, 1.0,2.5, 5.0, 10.0, 15.0, 25.0,and 50.0 milligrams of the active ingredientfor the symptomatic adjustment of the dosage to the patient to betreated. An effective amount of the drug is ordinarily supplied at adosage level of from about 0.002 mg. to about 50 mg./kg. of body weightper day. Preferably the range is from about 0.01 mg. to 7 mg./kgs. ofbody weight per day. These dosages are well below the toxic dose of theproduct. Capsules containing the product of this invention can beprepared by mixing an active compound of the present invention withlactose and magnesium stearate, calcium stearate, starch, talc, or othercarriers, and placing the mixture in gelatin capsule. Tablets may beprepared by mixing the active ingredient with conventional tabletingingredients such as calciuim phosphate, lactose, corstarch or magnesiumstearate. The liquid forms in suitably flavored suspending or dispersingagents such as the synthetic and natural gums, for example, tragacanth,acacia, methylcellulose and the like. Other dispersing agents which canbe employed include glycerin and the like. For parenteraladministration, suitably prepared implants or sterile suspensions andsolutions are desired. Isotonic preparations which generally containsuitable preservative are employed when intravenous administration isdesired.

For the treatment of acne vulgaris, seborrhea, female hirsutism, thecompounds of the present invention can be administered in the formula ofpharmaceutical composition comprising the active compound in combinationwith a pharmacologically acceptable carrier adapted for topicaladministration. Parenteral administration is also applicable. Thesetopical pharmaceutical compositions can be in the form of a cream,ointment, gel or aerosol formulation adapted for application to theskin. These topical pharmaceutical compositions containing the compoundsof the present invention ordinarily include about 0.1% to 15%,preferably about 5%, of the active compound, in admixture with about 95%of vehicle.

A method for preparing the novel anilide derivatives of17β-carboxy-3-oxo-4-azasteroids of the present invention, alreadydescribed above in general terms, may be further illustrated by thefollowing examples and synthetic procedure.

A synthetic procedure for these anilides is: ##STR5##

As seen in the above diagram, the 2-thiopyridyl intermediate (A, B or C)is reacted with an aniline, or substituted aniline, at room or elevatedtemperature, e.g. 25°-150° C., in the presence of a basic catalyst, e.g.an excess of the starting aniline, for a sufficient time, e.g. 6-24hours, to form the desired anilide (see Examples 1-3). Conventionalworkup procedures are utilized to isolate and purify the new anilide.

Further, the new anilide can be subjected to a secondary reaction toyield another new anilide. For example see Examples 4-6. In Example 4,the carboxamido nitrogen is further methylated to form the N-methylanalog. In Example 5, the 4-amino anilide is acylated to yield the4-isobutyloxyamino-phenyl analog. In Example 6, the 4-carbomethoxyanilide is saponified to the 4-carboxy analog. Thus, by starting with asubstituted anilide, containing a functional group X, Y, Z, which can befurther modified by a subsequent synthetic reaction, further newanilides can be obtained.

The following are preparations of intermediates useful in the inventionand examples of compounds of the invention, which should not beconstrued to be limits on the scope or spirit of the instant invention.

Preparation of Intermediates

A. S-2'-pyridyl-3-oxo-4-aza-4-methyl-5α-androstane-17β-thiocarboxylate

To a solution of 3-oxo-4-aza-4-methyl-5α-androstane-17β-carboxylic acid(7.0 g, 21 mmol) in toluene (300 ml) was added aldrithiol (14.7 g, 66.7mmol) and triphenylphosphine (16.49 g, 62.8 mmol). After stirring thereaction mixture overnight at room temperature, the reaction mixture wasconcentrated under vaccum and purified by column chromatography oversilica gel using 10% acetone/methylene chloride as eluant to give 6.0 gof pure product.

B. S-2'-pyridyl-3-oxo-4-aza-5α-androst-1-ene-17β-thiocarboxylate

To a solution of 3-oxo-4-aza-5α-androst-1-ene-17β-carboxylic acid (10.0g, 31.5 mmol) in toluene (60 ml) was added aldrithiol (14 g, 63.5 mmol)and triphenylphosphine (316 g, 61 mmol). After stirring the reactionmixture for overnight at room temperature, the product precipitated outof solution and was filtered (8.4 g).

C. S-2'-pyridyl-3-oxo-4-aza-5α-androstane-17β-thiocarboxylate

To a solution of 3-oxo-4-aza-5α-androstane-17β-carboxylic acid (20.0 g,62.7 mmol) in toluene (120 ml) was added aldrithiol (28 g, 127 mmol) andtriphenylphosphine (32 g, 122 mmol). After stirring the reaction mixturefor overnight at room temperature, the product precipitated out ofsolution and was filtered (20 g), Mp 247°-249° C.

EXAMPLE 1 ##STR6## N-phenyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide

S-2'-pyridyl-3-oxo-4-aza-5α-androst-1-ene-17β-thiocarboxylate (205 mg,0.5 mmol) was dissolved in aniline (1 ml) and solution heated at 130°for overnight. The reaction mixture was cooled and purified bypreperative silica gel tlc (30% acetone/methylene chloride) to give puretitled product which was recrystallized from acetonitrile. Mp 293°-295°C. Mass spec. (MS) M⁺ calculated 392.55; observed 393 (m+1). Anal. calcdfor C₂₅ H₃₂ N₂ O₂, C 76.49; H 8.21; N 7.14; Found C 76.59; H 8.26, N7.13

EXAMPLE 2 ##STR7##N-4-aminophenyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide

S-2'-pyridyl-3-oxo-4-aza-5α-androst-1-ene-17β-thiocarboxylate (200 mg)was dissolved in THF (25 ml) and to this p-phenylene diamine (200 mg)was added. After stirring the reaction mixture at reflux temperature for6 hrs, the reaction mixture was cooled to room temperature and left forovernight. Reaction mixture was concentrated and purified by prep.silica gel tic. Titled product (140 mg) was recrystallized from hotmethanol, Mp 259°-262° C. Mass spec. (MS) M⁺ calculated 407.56; observed408 (m+1). Anal. calcd for C₂₅ H₃₃ N₃ O₂ •0.3 H₂ O, C 72.71; H 8.20; N10.18; Found C 72.89; H 8.01, N 10.27.

EXAMPLE 3 ##STR8##N-2-carbomethoxyphenyl-3-oxo-4-aza-5α-androstane-17β-carboxamide

S-2'-pyridyl-3-oxo-4-aza-5β-androstane-17β-thiocarboxylate (207 mg, 0.5mmol) was dissolved in toluene (4 ml) and to this 2-methyl anthranilate(199.5 mg, 1.32 mmol) and silver trifluoromethanesulfonate (129 mg, 0.5mmol) were added. After stirring the reaction mixture at roomtemperature for 2 days, the reaction mixture was concentrated,partitioned between methylene chloride and water, methylene chloridelayer was washed with 5% aq. NH₄ OH, brine, dried, concentrated andpurified by prep. silica gel tlc. Titled product was recrystallized fromhot ethylate acetate, Mp 128°-129° C. Mass spec. (MS) M⁺ calculated452.58; observed 452. Anal.. calcd for C₂₇ H₃₆ N₂ O₄ •0.2 H₂ O, C 71.08;H 8.04; N 6.14; Found C 71.08; H 8.03, N 5.90.

EXAMPLE 4 ##STR9##N-methyl-N-4-carbomethoxyphenyl-3-oxo-4-aza-4-methyl-5α-androstane-17β-carboxamide

N-4-carboxymethylphenyl-3-oxo-4-aza-5α-androstane-17β-carboxylate (185mg, 0.41 mmol) was dissolved in 10 ml of DMF and mg of NaH (80%dispersion in mineral oil) was added. After stirring the reactionmixture for 2 hrs at room temperature, 100 micro liter methyl iodide wasadded. The reaction mixture was stirred further at room temperature for1 hr, excess of NaH decomposed by careful addition of water, extractedwith ethylacetate and organic layer was washed with water, dried andconcentrated to give yellow residue. The titled product was purified bycolumn silica gel tlc (30% acetone/CH₂ Cl₂), Mp 149°-150° C. Mass spec.(MS) M⁺ calculated 480.63; observed 480. Anal. calcd for C₂₉ H₄₀ N₂ O₄•0.8 H₂ O, C 72.47; H 8.39; N 5.83; Found C 70.36; H 8.08, N 5.55.

EXAMPLE 5 ##STR10##N-(4-isobutyramidophenyl)-3-oxo-4-aza-4-methyl-5α-androstane-17.beta.-carboxamide

To a solution ofN-4-aminophenyl-3-oxo-4-aza-4-methyl-5α-androstane-17β-carboxamide (80mg, 0.195 mmol) in methylene chloride (10 ml) was added DMAP (71.37 mg,0,585 mmol), pyridine (157 micro liter) and isobutyric anhydride (161.47micro liter, 0.975 mmol). After stirring the reaction mixture for 40min. at room temperature, the reaction mixture was diluted with 30 ml ofmethylene chloride, washed with aq. NaHCO₃, aq. HCl, water, brine, driedand concentrated. Residue was purified to yield rifled product bycrystallization from ethyl acetate/methylene chloride, Mp 260°-261° C.Mass spec. (MS) M⁺ calculated 493.70; observed 495 (m+2). Anal. calcdfor C₃₀ H₄₃ N₃ O₃, C 72.99; H 8.78; N 8.31; Found C 72.96; H 8.70, N8.34.

EXAMPLE 6 ##STR11##N-(4-carboxyphenyl)-3-oxo-4-aza-5α-androstane-17β-carboxamide

N-4-carboxymethyphenyl-3-oxo-4-aza-5α-androstane-17β-carboxamide (100mg) was dissolved in methanol (10 ml) and 4 ml of aq. KOH was added.After stirring the reaction mixture for 8 hrs at 50°, the reactionmixture was cooled to room temperature, acidified with aq. HCl andmethanol removed under vacuum. The solid obtained was filtered and driedto yield titled product, Mp 355°-357° C. ##STR12##

EXAMPLE 7 ##STR13##7β-Methyl-3-oxo-4-aza-5α-androstane-17β-(N-phenyl)carboxamide

The intermediate XII is reacted with aldrithiol/PPh₃ analogously asdescribed above to give the corresponding 2-thio-pyridylester.

This in turn is reacted with an excess of aniline at elevatedtemperature, e.g. 100°-150° C. to yield the above-titled7β-methyl-azasteroidal anilide.

Similarly, using other substituted anilines, other azasteroidal anilidescan be produced as described herein.

Preparation of the Starting Material XII

As seen in the Flowsheets A and B, pregnenolone-3-acetate P is firstreduced to the alcohol II by sodium borohydride in ethanol at -10° to 0°C. The alcohol II is then protected by a dimethyl-t-butyl silyl (TBS)group in DMF with TBS chloride and imidazole as a base at roomtemperature. The protected alcohol is then oxidized to the corresponding5-en-7-one III by treatment with hydrogen t-butyl peroxide and chromiumhexacarbonyl in e.g., acetonitrile, at reflux. The 7-methyl group can beintroduced at this point by a Grignard reaction using e.g., methylmagnesium chloride in e.g., anhydrous THF at 0° to -10° C. to producethe 7-methyl-7-hydroxy adduct IV. This is then oxidized with e.g.aluminum isopropoxide and cyclohexanone (Oppenauer oxidation conditions)in refluxing toluene solvent to produce the 7-methyl-4,6-dien-3-one V.This in turn is reduced via e.g., metal-ammonia, THF and toluene at -78°C. to selectively yield the 7-beta-methyl-5-en-3-one VI. In the nextstep the delta-5 double bond is isomerized to the 4-ene by use of DBU(1,8-diazabicyclo 5.4.0! undec-7-ene) in e.g. refluxing tetrahydrofuran(THF) to produce the 7-methyl-4-ene-3-one, VII. The A ring is nextcleaved by treatment with e.g. potassium permanganate, sodium periodatein t-butyl alcohol at 80° C. to produce the corresponding seco-acidVIII.

Treatment of the seco-acid with ammonium acetate in glacial acetic acidat 120° C. yields e.g., the 7-methyl-4-aza-pregn-5-en-3-one IX. This inturn is selectively reduced with e.g., PtO₂, to remove the 5-double bondto produce the 5α-hydrogen compound X. The TBS protecting group is nextremoved by aqueous HF in acetonitrile at room temperature and thenoxidized by tetrapropylammonium perruthenate/4-methylmorpholine N-oxidein methylene chloride at room temperature to yield the 17-acetylcompound XI. This is treated with a sodium hypobromite/sodium hydroxidesolution in dioxane at 10°-15° C. to form the starting intermediate17-carboxylic acid XII, mp. 311°-312+ C. This is then used as describedabove to make the 2-thiopyridyl ester and the resulting azasteroidalanilides.

The 1,2-double bond in the A ting can be introduced into XII by DDQoxidation (see procedure in U.S. Pat. No. 5,084,574) to produce XIII,mp. 328°-330° C. Formation of the 2-thiopyridyl intermediate XIV,analogously as described above, and reaction with aniline or substitutedanilines as described above produces the corresponding anilides, XVwhere Ra represents X, Y, Z substituents on the aniline ring.

What is claimed is:
 1. A compound of the formula: ##STR14## wherein: Ris H, CH₃, or C₂ H₅ ;R¹ is H, C₁ -C₁₀ alkyl, or phenyl; and X, Y and Zindependently represent --H; SH; --SC₁ -C₄ alkyl; --C₂ -C₁₀ acyl; aryl;--CONR² R³ where R² and R³ independently are H, C₁₋₈ alkyl, C₃₋₈cycloalkyl, or aryl; --NHCOR² ; --OCOR² ; --NR² (CO)R³ ; --NR² (CO)NHR³; --NHSO₂ R² ; --OR² ; --NR² R³ ; --CO₂ R² ;provided that X, Y, and Zcannot simultaneously be --H when R¹ is --H or C₁₋₁₀ alkyl, and providedfurther that X, Y, and Z cannot simultaneously be --H when R¹ is phenyland R⁴ is --H or methyl; R⁴ is selected from: alpha-hydrogen andbeta-hydrogen or beta-C₁ -C₄ alkyl; wherein aryl is phenyl; and whereinthe dashed line can represent a double bond when present; and wherein atleast two of X, Y and Z are hydrogen; and pharmaceutically acceptablesalts thereof.
 2. The compound selected from the group consistingof:N-(4-hydroxyphenyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamideN-(3-hydroxyphenyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamideN-(2-hydroxyphenyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamidephenyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide,N-(4-aminophenyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide,N-(3-aminophenyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide,N-(2-aminophenyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide,N-(4-carbomethoxy)phenyl-3-oxo-4-aza-5α-androstane-17β-carboxamide,N-(4-carbomethoxy)phenyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide,N-(4-carboxyphenyl)-3-oxo-4-aza-5α-androstane-17β-carboxamide,N-(4-carbomethoxy)phenyl-N-methyl-3-oxo-4-methyl-4-aza-5α-androstane-17β-carboxamide,N-(4-carbomethoxy)phenyl-N-methyl-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,N-(2-carbomethoxy)phenyl-3-oxo-4-aza-5α-androstane-17β-carboxamide,N-(2-carbomethoxy)phenyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide,N-(4-aminophenyl)-3-oxo-4-aza-5α-androstane-17β-carboxamide,N-(4-aminophenyl)-3-oxo-4-methyl-4-aza-5α-androstane-17β-carboxamide,N-4-acetamidophenyl-N-acetyl-3-oxo-4-methyl-4-aza-5α-androstane-17.beta.-carboxamide,N-(4-acetamido)phenyl-3-oxo-4-methyl-4-aza-5α-androstane-17β-carboxamide,N-(4-acetamidophenyl-3-oxo-4-aza-5α-androstane-17β-carboxamide,N-(4-pivalamido)phenyl-3-oxo-4-methyl-4-aza-5α-androstane-17β-carboxamide,andN-(4-isobutyramido)phenyl-3-oxo-4-methyl-4-aza-5α-androstane-17β-carboxamide.3. The compound selectedfromN-4-aminophenyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, andN-(4-isobutyramidophenyl)-3-oxo-4-aza-4-methyl-5α-androstane-17β-carboxamide.